Meshes coated with extracellular matrix (ECM)-derived hydrogels, cell-growth scaffolds and related methods are described herein.
The host response to surgically implanted biomaterials is a complex, temporally regulated process that is a critical determinant of functional outcome. Biomaterial devices may be relatively simple, such as knitted mesh constructs used for hernia repair, pelvic floor repair, and/or breast reconstruction, or highly complex, such as pacemaker electrodes. The host tissue response to any implanted device occurs through a host-material surface interaction and resultant downstream tissue remodeling within and around the device. Non-degradable synthetic polymers used for long term implantation, such as polytetrafluoroethylene (PTFE), polyethylene terephthalate, and polypropylene, elicit a classic foreign body response following implantation.
The foreign body reaction has been well-characterized from a histopathologic perspective, and components of the innate immune response play a critical role. Innate immune cell involvement begins with an acute inflammatory phase dominated by polymorphonuclear cells, followed by peripheral blood monocyte recruitment, and monocyte differentiation to macrophages that accumulate at the biomaterial surface. Inability to eliminate the foreign material with resultant persistent exposure to a non-degradable or slowly degradable material results in chronic inflammation and a mature foreign body reaction. Macrophage fusion into multinucleated foreign body giant cells and eventual fibrotic scar tissue deposition are hallmarks of this response.
Alternatively, surgical mesh materials composed of naturally occurring extracellular matrix (ECM) typically result in a non-fibrotic response following implantation. ECM scaffolds are prepared via decellularization of various warm-blooded mammalian tissues including, but not limited to, dermis, small intestinal submucosa, pericardium, and urinary bladder. The decellularization process disrupts and removes the cellular components of the tissue, which would otherwise initiate a robust pro-inflammatory response, and ideally leaves the remaining ECM intact. The ECM is a highly-conserved and complex assembly of structural and biochemically functional molecules that represent a cell-friendly micro-environmental niche. The innate immune response to an implanted ECM scaffold is histologically similar to the response to synthetic materials and is characterized by an accumulation of macrophages within and around the implanted ECM. However, non-crosslinked ECM scaffolds that are sufficiently decellularized are rapidly degraded and replaced with site-appropriate host tissue rather than fibrotic scar (see, e.g., Keane et al., “Consequences of Ineffective Decellularization of Biologic Scaffolds on the Host Response,” Biomaterials 33:1771-81 (2012)). The mechanisms of ECM scaffold remodeling are only partially understood, but studies have shown that immune activation processes are critical determinants of the downstream remodeling outcome. Despite the benefits of ECM-based products, a shortcoming to those products is their lack of mechanical strength. Thus, ECM-only products are not suitable solutions to the problem of the inflammatory response seen with synthetic meshes.
A robust and persistent macrophage infiltrate is found after implantation of both non-degradable synthetic polymers and degradable ECM, however, the remodeling outcome diverges considerably. A potential cause of the disparate host response is the effect of the biomaterial upon differential macrophage activation pathways. Macrophages may be polarized along a spectrum of two contrasting functional phenotypes: the classically activated pro-inflammatory M1 phenotype associated with host defense and the foreign body response, or the alternatively activated M2 phenotype associated with constructive tissue remodeling. Macrophage polarization has been studied in numerous biological contexts, including tumor growth, fetal development, and the host response to implanted biomaterials. Macrophages involved in constructive ECM remodeling present a greater proportion of the M2 phenotype compared to the phenotypic profile in the presence of non-degradable synthetic materials or chemically crosslinked, slowly degradable ECM, both of which show a dominant M1 response.
The gold standard for biomaterials used in ventral hernia repair are synthetic polymers, notably knitted polypropylene surgical mesh. Such synthetic materials have properties desirable for hernia repair such as high mechanical strength and efficient incorporation of the mesh into the surrounding host tissue. However, the inevitable foreign body reaction to polypropylene is associated with less desirable sequelae such as fibrosis, decreased tissue compliance, occasional fistula formation, and adhesions. Any of these events may result in patient discomfort and/or mesh explanation. Strategies to mitigate these events are of great interest. Accordingly, there is a need in the art for meshes suitable for implantation that have high mechanical strength and can be quickly incorporated into a site of injury, but that also have a lower propensity for chronic pain, contraction, restricted movement, and complications due to foreign body response and fibrosis.